Invasive margin tissue-resident macrophages of high CD163 expression impede responses to T cell-based immunotherapy

Marit J van Elsas; Camilla Labrie; Anders Etzerodt; Pornpimol Charoentong; Jordi J C van Stigt Thans; Thorbald Van Hall; Sjoerd H van der Burg

doi:10.1136/jitc-2022-006433

Invasive margin tissue-resident macrophages of high CD163 expression impede responses to T cell-based immunotherapy

J Immunother Cancer. 2023 Mar;11(3):e006433. doi: 10.1136/jitc-2022-006433.

Authors

Marit J van Elsas¹, Camilla Labrie¹, Anders Etzerodt², Pornpimol Charoentong³, Jordi J C van Stigt Thans¹, Thorbald Van Hall¹, Sjoerd H van der Burg⁴

Affiliations

¹ Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands.
² Department of Biomedicine, Aarhus University, Aarhus, Denmark.
³ Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴ Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands shvdburg@lumc.nl.

Abstract

Background: Primary and secondary resistance is a major hurdle in cancer immunotherapy. Therefore, a better understanding of the underlying mechanisms involved in immunotherapy resistance is of pivotal importance to improve therapy outcome.

Method: Here, two mouse models with resistance against therapeutic vaccine-induced tumor regression were studied. Exploration of the tumor microenvironment by high dimensional flow cytometry in combination with therapeutic in vivo settings allowed for the identification of immunological factors driving immunotherapy resistance.

Results: Comparison of the tumor immune infiltrate during early and late regression revealed a change from tumor-rejecting toward tumor-promoting macrophages. In concert, a rapid exhaustion of tumor-infiltrating T cells was observed. Perturbation studies identified a small but discernible CD163^hi macrophage population, with high expression of several tumor-promoting macrophage markers and a functional anti-inflammatory transcriptome profile, but not other macrophages, to be responsible. In-depth analyses revealed that they localize at the tumor invasive margins and are more resistant to Csf1r inhibition when compared with other macrophages. In vivo studies validated the activity of heme oxygenase-1 as an underlying mechanism of immunotherapy resistance. The transcriptomic profile of CD163^hi macrophages is highly similar to a human monocyte/macrophage population, indicating that they represent a target to improve immunotherapy efficacy.

Conclusions: In this study, a small population of CD163^hi tissue-resident macrophages is identified to be responsible for primary and secondary resistance against T-cell-based immunotherapies. While these CD163^hi M2 macrophages are resistant to Csf1r-targeted therapies, in-depth characterization and identification of the underlying mechanisms driving immunotherapy resistance allows the specific targeting of this subset of macrophages, thereby creating new opportunities for therapeutic intervention with the aim to overcome immunotherapy resistance.

Keywords: Immunotherapy; Macrophages; Tumor Escape; Tumor Microenvironment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Humans
Immunotherapy / methods
Macrophages
Mice
Neoplasms* / pathology
T-Lymphocytes*
Tumor Microenvironment

Substances

CD163 antigen